Neurons in the central nervous system can be broadly classified into two strikingly different systems: 1) highly organized, hierarchical systems and 2) diffuse, non-specific systems. The norepinephrine-locus coeruleus (NE-LC) system best typified the second category. In the past neurophysiologists have focused primarily on the first category. Recent work on the NE-LC system indicates that there are fundamental differences in the synaptic mechanisms involved in this system. For instance it has been proposed that NE can simultaneously inhibit spontaneous activity and yet enhance the response to excitatory synaptic inputs thus increasing the signal-to-noise ratio of neurons. A satisfactory explanation for these seemingly paradoxical effects is not available. Our research will focus on the action of NE. We have preliminary evidence in the hippocampal slice that NE exerts a direct action on relay neurons to increase the signal to noise ratio, in agreement with previous proposals, and an indirect action involving a blockade of inhibitory pathways. The direct action appears to involve a cyclic AMP modulation of a Ca++ activated K+ conductance (GK(Ca)), while the site of action on inhibitory pathways is unclear. Both of these actions stand in marked contrast to the traditional view that NE is an inhibitory transmitter. The specific goals of this proposal, which will rely on intracellular recording are 1) to elucidate the mechanism and receptor type underlying the direct and indirect action of NE in the hippocampal slice, 2) to determine if similar results can be obtained from other cell types in slice preparations, 3) to determine if electrical stimulation of the NE-LC pathway in vivo mimics the effects of bath applied NE. The NE-containing locus coeruleus neurons are thought to be involved in such global brain functions as arousal and transitions between behavioral states as well as in numerous psychiatric disorders. The proposed experiments will not only provide deeper insight in the neurophysiological and neuropharmacological organization of NE in cortical regions and how NE is involved processing information, but also may well provide important clues about the role of NE in normal and abnormal behavior.